Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

Irit Reichenstein, Chen Eitan, Sandra Diaz-Garcia, Guy Haim, Iddo Magen, Aviad Siany, Mariah L. Hoye, Natali Rivkin, Tsviya Olender, Beata Toth, Revital Ravid, Amitai D. Mandelbaum, Eran Yanowski, Jing Liang, Jeffrey K. Rymer, Rivka Levy, Gilad Beck, Elena Ainbinder, Sali M.K. Farhan, Kimberly A. LennoxNicole M. Bode, Mark A. Behlke, Thomas Möller, Smita Saxena, Cristiane A.M. Moreno, Giancarlo Costaguta, Kristel R. van Eijk, Hemali Phatnani, Ammar Al-Chalabi, A. Nazli Başak, Leonard H. van den Berg, Orla Hardiman, John E. Landers, Jesus S. Mora, Karen E. Morrison, Pamela J. Shaw, Jan H. Veldink, Samuel L. Pfaff, Ofer Yizhar, Christina Gross, Robert H. Brown, John M. Ravits, Matthew B. Harms, Timothy M. Miller, Eran Hornstein

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Abstract

Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.

Original languageEnglish
Article numbereaav5264
JournalScience translational medicine
Volume11
Issue number523
DOIs
StatePublished - Dec 18 2019

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    Reichenstein, I., Eitan, C., Diaz-Garcia, S., Haim, G., Magen, I., Siany, A., Hoye, M. L., Rivkin, N., Olender, T., Toth, B., Ravid, R., Mandelbaum, A. D., Yanowski, E., Liang, J., Rymer, J. K., Levy, R., Beck, G., Ainbinder, E., Farhan, S. M. K., ... Hornstein, E. (2019). Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology. Science translational medicine, 11(523), [eaav5264]. https://doi.org/10.1126/scitranslmed.aav5264